Han Xu, Chaolong Xu, Ying Zou, Xin Duan, Minhan Song, Xiaodi Han, Tianyu Song, Yang Liu, Fang Fang
This study represents an extension of our earlier work by incorporating an additional 18 cases, which expands the genetic and phenotypic spectrum of DNM1L-related disorders. It identifies "hemiconvulsion-hemiplegia-epilepsy syndrome" as a distinct feature and potential prognostic indicator for middle domain variants. The established genotype-phenotype patterns, based on protein domains and ethnic differences, provide critical insights for precise diagnosis and management.
AIMS: To summarize the clinical and genetic characteristics of DNM1L-related disorders and explore genotype-phenotype correlations and prognosis.
METHODS: We retrospectively analyzed clinical data from 18 children with DNM1L variants diagnosed between 2015 and October 2025. Combined with systematic literature review (2007-October 2025) to analyze reported DNM1L variant types and clinical phenotypes.
RESULTS: The cohort included 18 children (10 male, 8 female) with a median onset age of 3.5 years. Epilepsy occurred in 88.9% of patients, with 72.2% developing super-refractory status epilepticus; 66.7% had dystonia. Most patients exhibited brain MRI and EEG abnormalities. Eight novel pathogenic variants were identified (four missense, three frameshift, one compound heterozygous). Notably, eight patients with middle domain variants (primarily p.Arg403Cys) presented a novel "hemiconvulsion-hemiplegia-epilepsy syndrome" phenotype. At last follow-up, 83.3% had a modified Rankin Scale score ≥4, indicating severe disability and poor prognosis. Literatures review confirmed DNM1L variants are predominantly missense, with the middle domain as a hotspot. The p.Arg403Cys variant is recurrent and highly prevalent in the Chinese. Middle domain variants are more common in Asians, while GTPase domain variants are more frequent in Europeans. Missense variants in the middle domain correlated with higher rates of neurological dysfunction and mortality.
CONCLUSIONS: This study represents an extension of our earlier work by incorporating an additional 18 cases, which expands the genetic and phenotypic spectrum of DNM1L-related disorders. It identifies "hemiconvulsion-hemiplegia-epilepsy syndrome" as a distinct feature and potential prognostic indicator for middle domain variants. The established genotype-phenotype patterns, based on protein domains and ethnic differences, provide critical insights for precise diagnosis and management.